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| ImageFile = Wortmannin.svg |
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|Section1= {{Chembox Identifiers |
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| IUPACName = 1α-(Methoxymethyl)-3,7,17-trioxo-2-oxa-6,4-(epoxymetheno)androsta-5,8-dien-11α-yl acetate |
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| CASNo=19545-26-7 |
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| SystematicName = (1''S'',6b''R'',9a''S'',11''R'',11b''R'')-1-(Methoxymethyl)-9a,11b-dimethyl-3,6,9-trioxo-1,6,6b,7,8,9,9a,10,11,11b-decahydro-3''H''-furoindenobenzopyran-11-yl acetate |
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| PubChem=5691 |
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| SMILES=CC(=O)OC1CC2(C(CCC2=O)C3=C1C4 (C(OC(=O)C5=COC(=C54)C3=O)COC)C)C |
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| Section1 ={{Chembox Identifiers |
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| IUPHAR_ligand = 6060 |
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| CASNo_Ref = {{cascite|correct|??}} |
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| CASNo =19545-26-7 |
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| UNII = XVA4O219QW |
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| ChEMBL = 428496 |
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| ChEBI = 52289 |
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| ChemSpiderID = 276037 |
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| SMILES = O=C\3c2occ1C(=O)O((c12)(/C5=C/34(C(=O)CC4)(C)C5OC(=O)C)C)COC |
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| StdInChI = 1S/C23H24O8/c1-10(24)30-13-7-22(2)12(5-6-14(22)25)16-18(13)23(3)15(9-28-4)31-21(27)11-8-29-20(17(11)23)19(16)26/h8,12-13,15H,5-7,9H2,1-4H3/t12-,13+,15+,22-,23-/m0/s1 |
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| StdInChIKey = QDLHCMPXEPAAMD-QAIWCSMKSA-N |
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| C=23 | H=24 | O=8 |
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| Formula=C<sub>23</sub>H<sub>24</sub>O<sub>8</sub> |
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| MolarMass=428.43186 |
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'''Wortmannin''', a steroid metabolite of the fungi '']'', '']'', is a non-specific, ] inhibitor of ]s (PI3Ks). It has an ''in vitro'' ] (''IC''<sub>50</sub>) of around 5 nM, making it a more potent inhibitor than ], another commonly used ]. It displays a similar potency ''in vitro'' for the ], ], and ] PI3K members although it can also inhibit other PI3K-related enzymes such as ], ], some ]s, ] (MLCK) and ] (MAPK) at high concentrations<ref name="pmid11395417">{{cite journal | vauthors = Vanhaesebroeck B, Leevers SJ, Ahmadi K, Timms J, Katso R, Driscoll PC, Woscholski R, Parker PJ, Waterfield MD | title = Synthesis and function of 3-phosphorylated inositol lipids | journal = Annual Review of Biochemistry | volume = 70 | pages = 535–602 | date = 2001 | pmid = 11395417 | doi = 10.1146/annurev.biochem.70.1.535 }}</ref><ref name="pmid9131167">{{cite book | vauthors = Ferby I, Waga I, Kume K, Sakanaka C, Shimizu T | title = Platelet-Activating Factor and Related Lipid Mediators 2 | chapter = PAF-Induced MAPK Activation is Inhibited by Wortmannin in Neutrophils and Macrophages | series = Advances in Experimental Medicine and Biology | volume = 416 | pages = 321–6 | date = 1996 | pmid = 9131167 | doi = 10.1007/978-1-4899-0179-8_51 | isbn = 978-1-4899-0181-1 }}</ref> Wortmannin has also been reported to inhibit members of the ] family with ''IC''<sub>50</sub> in the same range as for PI3K.<ref name="pmid17135248">{{cite journal | vauthors = Liu Y, Jiang N, Wu J, Dai W, Rosenblum JS | title = Polo-like kinases inhibited by wortmannin. Labeling site and downstream effects | journal = The Journal of Biological Chemistry | volume = 282 | issue = 4 | pages = 2505–11 | date = January 2007 | pmid = 17135248 | doi = 10.1074/jbc.M609603200 | doi-access = free }}</ref> The half-life of wortmannin in tissue culture is about 10 minutes due to the presence of the highly reactive C20 carbon that is also responsible for its ability to covalently inactivate PI3K. Wortmannin is a commonly used ] reagent that has been used previously in research to inhibit ], ] and cell proliferation.<ref name="pmid15664519">{{cite journal | vauthors = Liu Y, Shreder KR, Gai W, Corral S, Ferris DK, Rosenblum JS | title = Wortmannin, a widely used phosphoinositide 3-kinase inhibitor, also potently inhibits mammalian polo-like kinase | journal = Chemistry & Biology | volume = 12 | issue = 1 | pages = 99–107 | date = January 2005 | pmid = 15664519 | doi = 10.1016/j.chembiol.2004.11.009 | doi-access = free }}</ref><ref name="pmid22056625">{{cite journal | vauthors = Kim SH, Jang YW, Hwang P, Kim HJ, Han GY, Kim CW | title = The reno-protective effect of a phosphoinositide 3-kinase inhibitor wortmannin on streptozotocin-induced proteinuric renal disease rats | journal = Experimental & Molecular Medicine | volume = 44 | issue = 1 | pages = 45–51 | date = January 2012 | pmid = 22056625 | pmc = 3277897 | doi = 10.3858/emm.2012.44.1.004 }}</ref> |
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'''Wortmannin''', a furanosteroid metabolite of the fungi '']'', '']''<ref>Source: </ref>, |
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is a specific, ] inhibitor of ]s (]s). It has an ''in vitro'' ] (''IC''<sub>50</sub>) of around 5 nM, making it a more potent inhibitor than ], another commonly used ]. It displays a similar potency ''in vitro'' for the ], ], and ] PI3K members although it can also inhibit other PI3K-related enzymes such as ], ], some ]s, ] (MLCK) and ] (MAPK) at high concentrations <ref>Vanhaesebroeck B ''et al.'', (2001) Synthesis and function of 3-phosphorylated inositol lipids. Annu Rev Biochem.</ref><sup>,</sup><ref>Ferby I ''et al.'', 1996. Adv Exp Med Biol. PAF-induced MAPK activation is inhibited by wortmannin in neutrophils and macrophages.</ref> Wortmannin has also been reported to inhibit members of the ] family with ''IC''<sub>50</sub> in the same range as for PI3K.<ref>Liu Y ''et al.'', 2007. J. Biol Chem 282(4): 2505-11 Polo-like Kinases Inhibited by Wortmannin: Labeling Site and Downstream Effects</ref>. The half-life of wortmannin in tissue culture is about 10 minutes due to the presence of the highly reactive C20 carbon that is also responsible for its ability to covalently inactivate PI3K. Wortmannin is a commonly used ] reagent that has been used previously in research to inhibit ], ] and cell proliferation {{Citation needed|date=February 2007}}. |
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==Background: Phosphoinositide-3-kinase== |
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==Phosphoinositide-3-kinase== |
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] (PI3K) activates an important cell survival signaling pathway, and constitutive activation is seen in ovarian, head and neck, urinary tract, cervical and small cell lung cancer. PI3K signaling is attenuated by the phosphatase activity of the tumor suppressor PTEN that is absent in a number of human cancers. Inhibiting PI3K presents the opportunity to inhibit a major cancer cell survival signaling pathway and to overcome the action of an important deleted tumor suppressor, providing antitumor activity and increased tumor sensitivity to a wide variety of drugs. |
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Wortmannin is a ]; as such, it has detrimental influence on memory and impairs spatial learning abilities.<ref name="pmid12610654">{{cite journal | vauthors = Mizuno M, Yamada K, Takei N, Tran MH, He J, Nakajima A, Nawa H, Nabeshima T | title = Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation | journal = Molecular Psychiatry | volume = 8 | issue = 2 | pages = 217–24 | date = February 2003 | pmid = 12610654 | doi = 10.1038/sj.mp.4001215 | doi-access = | s2cid = 21168835 }}</ref><ref>{{cite journal | vauthors = Jiang X, Tian Q, Wang Y, Zhou XW, Xie JZ, Wang JZ, Zhu LQ | title = Acetyl-L-carnitine ameliorates spatial memory deficits induced by inhibition of phosphoinositol-3 kinase and protein kinase C | journal = Journal of Neurochemistry | volume = 118 | issue = 5 | pages = 864–78 | date = September 2011 | pmid = 21689104 | doi = 10.1111/j.1471-4159.2011.07355.x | doi-access = | s2cid = 45573586 }}</ref><ref>{{cite journal | vauthors = Kumar M, Bansal N | title = Fasudil hydrochloride ameliorates memory deficits in rat model of streptozotocin-induced Alzheimer's disease: Involvement of PI3-kinase, eNOS and NFκB | journal = Behavioural Brain Research | volume = 351 | pages = 4–16 | date = October 2018 | pmid = 29807069 | doi = 10.1016/j.bbr.2018.05.024 | s2cid = 44121036 }}</ref> |
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Phosphoinositide-3-kinase (]) activates an important cell survival signaling pathway, and constitutive activation is seen in ovarian, head and neck, urinary tract, cervical and small cell lung cancer. PI-3-K signaling is attenuated by the phosphatase activity of the tumor suppressor PTEN that is absent in a number of human cancers. Inhibiting PI-3-K presents the opportunity to inhibit a major cancer cell survival signaling pathway and to overcome the action of an important deleted tumor suppressor, providing antitumor activity and increased tumor sensitivity to a wide variety of drugs. |
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==Derivatives== |
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Wortmannin is a known and potent ]; as such, it was shown to have enhancing influence on memory and impair learning abilities.<ref>Molecular Psychiatry (2003) 8, 217–224; <i>Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation</i> |
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] research has been conducted to identify wortmannin ] that are more stable, while not losing its therapeutic effect.<ref name="pmid15252137">{{cite journal | vauthors = Ihle NT, Williams R, Chow S, Chew W, Berggren MI, Paine-Murrieta G, Minion DJ, Halter RJ, Wipf P, Abraham R, Kirkpatrick L, Powis G | title = Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling | journal = Molecular Cancer Therapeutics | volume = 3 | issue = 7 | pages = 763–72 | date = July 2004 | doi = 10.1158/1535-7163.763.3.7 | pmid = 15252137 | url = https://mct.aacrjournals.org/content/3/7/763.short | doi-access = free }}</ref> |
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M Mizuno</ref> {{Citation needed|date=August 2010}} |
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==Derivates== |
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===Sonolisib=== |
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In order to stabilize the Wortmannin molecule while not losing its therapeutic effect, numerous derivates were synthesized from Wortmannin<ref>: Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling, Nathan T. Ihle et al., Mol Cancer Ther. 2004;3:763-772</ref> |
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One of these, sonolisib (PX-866), has been shown to be an ] of PI-3 kinase with efficacy when delivered orally. Sonolisib was put in a phase 1 clinical trial by Oncothyreon.<ref name=Howes2007>{{cite journal | vauthors = Howes AL, Chiang GG, Lang ES, Ho CB, Powis G, Vuori K, Abraham RT | title = The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures | journal = Molecular Cancer Therapeutics | volume = 6 | issue = 9 | pages = 2505–14 | date = September 2007 | pmid = 17766839 | doi = 10.1158/1535-7163.MCT-06-0698 | doi-access = | s2cid = 36657063 }}</ref><ref name=Ph1-data2010>{{Dead link|date=May 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref name=NCT00726583>{{ClinicalTrialsGov|NCT00726583|Phase I Trial of Oral PX-866}}</ref> The clinical development plan for sonolisib includes both standalone and combination therapy in major human cancers.<ref> lifesciencesworld news</ref> In 2010, sonolisib was starting 4 phase II trials for ]s.<ref>{{cite news |url=http://www.medicalnewstoday.com/articles/206625.php |title=ONTY Starts Four-Phase II Trial Program With Its Oral PI3K Inhibitor |date=4 Nov 2010 }}{{Dead link|date=May 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> The company gave an update on its phase 2 trials in Jun 2012.<ref>{{Cite web |url=http://ir.oncothyreon.com/releasedetail.cfm?releaseid=679336 |title=Oncothyreon Announces Presentation of PX-866 Clinical Data at American Association of Clinical Oncology Annual Meeting. June 2012 |access-date=2016-03-17 |archive-date=2016-03-24 |archive-url=https://web.archive.org/web/20160324125545/http://ir.oncothyreon.com/releasedetail.cfm?releaseid=679336 |url-status=dead }}</ref> Phase 1 results (with docetaxel) published Aug 2013.<ref></ref> In July 2014 published results of a phase 2 trial (for NSCLC) concluded : "The addition of PX-866 to docetaxel did not improve PFS, response rate, or OS in patients with advanced, refractory NSCLC without molecular preselection".<ref>{{cite journal | vauthors = Levy B, Spira A, Becker D, Evans T, Schnadig I, Camidge DR, Bauman JE, Hausman D, Walker L, Nemunaitis J, Rudin CM, Halmos B, Bowles DW | title = A randomized, phase 2 trial of Docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic non-small-cell lung cancer | journal = Journal of Thoracic Oncology | volume = 9 | issue = 7 | pages = 1031–1035 | date = July 2014 | pmid = 24926548 | doi = 10.1097/JTO.0000000000000183 | doi-access = free }}</ref> In Sept 2015 as Phase 2 trial for recurrent ] reported not meeting its primary endpoint.<ref>{{cite journal | vauthors = Pitz MW, Eisenhauer EA, MacNeil MV, Thiessen B, Easaw JC, Macdonald DR, Eisenstat DD, Kakumanu AS, Salim M, Chalchal H, Squire J, Tsao MS, Kamel-Reid S, Banerji S, Tu D, Powers J, Hausman DF, Mason WP | title = Phase II study of PX-866 in recurrent glioblastoma | journal = Neuro-Oncology | volume = 17 | issue = 9 | pages = 1270–4 | date = September 2015 | pmid = 25605819 | pmc = 4588751 | doi = 10.1093/neuonc/nou365 }}</ref> |
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== References == |
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One of these, ], has been shown to be a novel, potent, irreversible, inhibitor of PI-3 kinase with efficacy when delivered orally. ] is currently in a phase 1 clinical trial by company. The clinical development plan for PX-866 includes both standalone and combination therapy in major human cancers.<ref> lifesciencesworld news: Oncothyreon initiates Phase 1 trial of PX-866 cancer compound</ref> |
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{{Reflist|2}} |
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==References== |
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{{Reflist}} |
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==External links== |
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==External links== |
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{{Commonscatinline|Wortmannin}} |
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